The regulation of β-cell mass in the status of nondiabetic obesity remains not well understood. We aimed to investigate the role of circulating exosome-like vesicles (ELVs) isolated from humans with simple obesity in the regulation of islet β-cell mass. Between June 2017 and July 2019, 81 subjects with simple obesity and 102 healthy volunteers with normal weight were recruited. ELVs were isolated by ultra-centrifugation. The proliferations of β-cells and islets were measured by 5-ethynl-2′-deoxyuridine (EdU). Protein components in ELVs were identified by Quantitative Proteomic Analysis and verified by Western blot and ELISA. The role of specific exosomal protein was analyzed by gain-of-function approach in ELVs released by 3T3-L1 preadipocytes. Circulating ELVs from subjects with simple obesity inhibited β-cell proliferation in vitro without affecting its apoptosis, secretion, and inflammation. The protein levels of Rictor and Omentin-1 were downregulated in circulating ELVs from subjects with simple obesity and associated with the obesity-linked pathologic conditions. The ELV-carried Omentin-1 and Omentin-1 protein per se were validated to increase β-cell proliferation and activate Akt signaling pathway. Moreover, Omentin-1 in ELVs was downregulated by insulin. The circulating ELVs may act as a negative regulator for β-cell mass in nondiabetic obesity through inhibiting β-cell proliferation. This effect was associated with downregulated Omentin-1 protein in ELVs. This newly identified ELV-carried protein could be a mediator linking insulin resistance to impaired β-cell proliferation and a new potential target for increasing β-cell mass in obesity and T2DM.

Obesity-induced inflammation, characterized by augmented infiltration and altered balance of macrophages, is a critical component of systemic insulin resistance. Chemokine-chemokine receptor system plays a vital role in the macrophages accumulation. CC-Chemokine Receptor-like 2 (Ccrl2) is one of the receptors of Chemerin, which is a member of atypical chemokine receptors (ACKR) family, reported taking part in host immune responses and inflammation-related conditions. In our study, we found ccrl2 expression significantly elevated in visceral adipose tissue (VAT) of high fat diet (HFD) induced obese mice and ob/ob mice. Systemic deletion of Ccrl2 gene aggravated HFD induced obesity and insulin resistance and ccrl2 mice showed aggravated VAT inflammation and increased M1/M2 macrophages ratio, which is due to the increase of macrophages chemotaxis in Ccrl2 deficiency mice. Cumulatively, these results indicate that Ccrl2 has a critical function in obesity and obesity-induced insulin resistance via mediating macrophages chemotaxis.

Adipocytes and immune cells are vital for the development of adipose tissue. Adipokines secreted by adipocytes regulate adipogenesis and body metabolism. Chemerin is one of the adipokines. However, the function and mechanism of chemerin in adipose tissue are not fully illuminated. Compared with wild type (WT) mice, Rarres2^-/- mice gained weight and significantly increased fat distribution in subcutaneous adipose tissue (SAT), rather than visceral adipose tissue (VAT) on high fat diet (HFD). PPARγ and C/EBPα, the master regulators of adipogenesis, were up-regulated in SAT and down-regulated in VAT in Rarres2^-/- mice comparing with WT mice. Inspite of chemerin deficiency or not, the ratio of adipocyte-progenitors to total cells and the differentiation capacity of adipocyte-progenitors were similar in SAT and VAT, but macrophage infiltration in VAT was more severe than in SAT in Rarres2^-/- mice. Furthermore, CD45⁺ immune cells supernatant from Rarres2^-/- SAT promoted the differentiation of adipocyte-progenitors and 3T3-L1 cells. Adipokine array assay of CD45⁺ immune cells supernatant revealed that metalloproteinase inhibitor 1 (TIMP1), an inhibitor of adipogenesis, was reduced in Rarres2^-/- SAT, but increased in Rarres2^-/- VAT. As we specifically knocked down chemerin in SAT, TIMP1 was down-regulated and adipogenesis was promoted with reducing infiltration of macrophages. The present study demonstrates that the effects of chemerin on adipose tissue is depot different, and specific knock down chemerin in SAT promote adipogenesis and improve glucose tolerance test (GTT) and insulin tolerance test (ITT). This suggests a potential therapeutic target for chemerin in the treatment of obesity related metabolic disorder.